1. Field of the Invention
The present invention relates to a method for treating inflammatory or degenerative diseases by administering to an individual a pharmaceutically effective amount of a mixed extract of Cibotii Rhizoma, Ledebouriellae Radix, Achyranthis Radix, Paeonia lactiflora Pall, and Glycyrrhizae Radix.
2. Description of the Related Art
Inflammation is a biological defense reaction against infection caused by external sources such as external physical and chemical stimuli, bacteria, fungi, viruses, and all sorts of allergens. The inflammatory response is part of innate immune responses, and as in other animals, the human innate immune responses begin when macrophages recognize patterns which present specifically on the cellular surface of pathogens as non-self and attack the pathogens. During the inflammatory response, blood plasma accumulate around the inflammatory site to dilute toxic products released by bacteria, blood stream increases, and symptoms such as erythema, pain, edema, fever and the like are involved.
These inflammatory responses involve various biochemical phenomena, and in particular, nitric oxide synthase (NOS) and cyclooxygenase (COX) which is related to prostaglandin biosynthesis are known to be important mediators of inflammatory responses. Among them, COX-1 is involved in the production of prostaglandin products (hereinafter referred to as “PG”) in the inflammatory site as well as in various normal organs and tissues of the human body, i.e. gastrointestinal tract or kidney and the like. In comparison, COX-2 is known to be an enzyme which functions only at sites of inflammation. It has been known that commercially available nonsteroidal anti-inflammatory drugs (referred to as “NSAIDs”) such as diclofenac, aspirin and ibuprofen, inhibit COX-1 and COX-2 at the same time or primarily COX-1, and thus, they inhibit PG not only in tissues with inflammation, when administered for long periods, but also inhibit PG that are essential for function maintenance in other tissues such as liver, gastrointestinal tract, or kidney at the same time, causing numerous adverse effects (Isselbcher et al., Harrison's Principles of Internal Medicine, (13th ed)2, pp 1543-1711).
According to Korea National Health and Nutrition Examination Survey in the years 1998 and 2001, arthritis was a chronic disease being common among adults aged 45 years or older, and the prevalence rate of arthritis increased with age, and in 65 years and over population, it accounted for 356.7 persons per one thousand people in 1998 and 364.2 persons per one thousand people in 2001 (Korea National Health and Nutrition Examination Survey, 2001, Ministry of Health and Welfare, Seoul, Korea, p 51). According to the recent “Senior Statistical Reports, 2010”, the ratio of Korean 65 years and over population is 11%, and the prevalence rate of chronic degenerative diseases increases along with the ageing of population structure, and the chronic disease of high annual prevalence rate is arthritis which accounts for 43.1% or more (Senior Statistical Reports, 2010, The Statistics Korea, Daejeon, Korea, p 5). Arthritis refers to joint inflammation, often involves pain, stiffness and edema, and its causes are degenerative changes, abnormality of immune system, infection, wound, disturbances of metabolism, etc., and there are more than one hundred kinds (Garner B C et al., 2011, Using animal models in osteoarthritis biomarker research, J Knee Surg 24: 251-264). Among them, osteoarthritis and rheumatoid arthritis (RA) account for 80% of the entire arthritis, and make up the largest part of burden caused by musculoskeletal diseases. When dividing factors associated with the onset of osteoarthritis into large groups, proteolytic enzymes, cytokines, and nitric oxide (NO) are known to be main factors (Wu W et al., 2010, Therapeutic effect of the saponin fraction from Clematis chinensis Osbeck roots on osteoarthritis induced by monosodium iodoacetate through protecting articular cartilage. Phytother Res 24: 538-546; Wesche-Soldato D E et al., 2007, The apoptotic pathway as a therapeutic target in sepsis, Curr Drug Targets 8: 493-500; Herrington C et al., 2008, Molecular and cellular themes in inflammation and immunology, J Pathol 214: 123-125; Campo G M et al., 2009, Glycosaminoglycans modulate inflammation and apoptosis in LPS-treated chondrocytes, J Cell Biochem 160: 83-92). The process of metabolism in cartilage tissues plays a pivotal role in the degeneration of cartilage tissues (Phitak T et al., 2009, The effects of p-hydroxycinnamaldehyde from Alpinia galanga extracts on human chondrocytes, Phytochemistry 7: 237-243), and representatively, matrix metalloproteinases (MMPs) are a proteolytic enzyme that destroys matrix components in bone and cartilage, and are expressed also in a pathological condition such as arthritis, and it has been known that MMPs play a major role in etiology (Janusz M J et al., 2001, Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors, Osteoarthritis Cartilage 9: 751-760; Okada A et al., 2009, Progress of research in osteoarthritis, Metalloproteinases in osteoarthritis, Clin Calcium 19: 1593-1601). Upon the onset of arthritis, MMPs of which expression increases are MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-7, and MMP-13, and in particular, it was reported that in cases of MMP-7 and MMP-13, their expression is increased in osteoarthritis (Yoshihara Y et al., 2000, Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis, Ann Rheum Dis 59: 455-461).
Recently, various drugs and treatment methods have been developed and used in the treatment of osteoarthritis, but, the main purpose of treatment is to relieve pain, maintain joint function, and prevent disability caused by dysfunction of joint. Treatment methods of arthritis are being focused on removal of pain by taking a simple analgesic, and when arthritis proceeds further and pain continues, anti-inflammatory analgesic drugs having strong anti-inflammatory effect are used. So far, many drugs having analgesic and anti-inflammatory effects have been developed, and include nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, aspirin, and ibuprofen. However, NSAIDs which are often used for treatment of arthritis have a problem that causes adverse effects to the digestive system, in particular, to a stomach, and this is because NSAIDs inhibit an stomach inner wall protective enzyme, cyclooxygenase 1 (COX-1), and a pain- and inflammation-causing enzyme, cyclooxygenase 2 (COX-2), at the same time. In addition, long-term use of NSAID can lead to a heartburn or ulcer which eventually causes perforation.
Disc pain diseases are an important disease of modern society, costing many billions of dollars of medical finances, and according to United States' National Health Statistics, it has been reported that more than 2% of the population have disc diseases, and five million people show symptoms of spine sprain (Premer, A., S, et, al., 1999; Andersson, G. B., 1999). Also in the South Korea, spine-related pains cause a huge loss in labor force and excessive health expenditure, leading to economic losses.
As biochemical changes, IL-1 of cytokines and proteolytic enzymes such as stromelysin and metalloproteinase (MMP) are found in degenerative disc or extruded disc, and IL-1 was assumed to promote synthesis of metalloproteinase, nitric oxide, prostaglandin E2, etc. in a normal disc and lead to disc degeneration (Kang, J. D., et, al., 1997). Injured discs or discs having degenerative changes become to lose their dynamic function, cause pains, and unlike skin inflammation, edema occur inside, pressure increases and compresses an inflammatory site and its surroundings. In addition, when inflammation occurs, spinal muscles around the lesion become tensed and compress the inflammatory site and its surroundings. This compression acts as a physical stimulus to the lesion, and causes larger inflammation. Accordingly, there is a need to develop natural products and materials which can have excellent efficacy in inflammation, arthritis and disc diseases in human bodies and of which the safety is guaranteed 100 percent.
Thus, the present inventors have made an effort to develop natural products having effective anti-inflammatory activity for arthritis or disc disease, and as a result, have found the fact that: a mixed extract of Cibotii Rhizoma, Ledebouriellae Radix, Achyranthis Radix, Paeonia lactiflora Pall and Glycyrrhizae Radix increased the survival rate of macrophages in vitro, decreased NO production effectively, exhibited significant anti-inflammatory effect by inhibiting COX-2, iNOS and MMP expressions, showed nerve cell regenerative and protective effects, exhibited pain-inhibitory effect in vivo, and inhibited arthritis edema and showed clinical pharmacological effect in patients of disc diseases. Accordingly, the present inventors identified that the mixed extract of Cibotii Rhizoma, Ledebouriellae Radix, Achyranthis Radix, Paeonia lactiflora Pall and Glycyrrhizae Radix could be used effectively for a method for treating inflammation, arthritis, or disc diseases, and completed the present invention based on the fact.